Proteolysis of lung elastin and other connective tissue proteins released from leukocytes is generally thought to cause the desctruction of the lung which is observed in pulmonary emphysema. The two major serine proteases of leukocytes, human leukocyte elastase and cathepsin G, will hydrolyze lung elastin. In addition of emphysema, elastase is involved in amyloidosis and chronic inflammation, while pancreatic elastase in involved in pancreatitis. Cathepsin G and other chymotrypsin-like enzymes from mast cells are speculated to play a role in inflammation and arthritis. The goal of this research is to develop an elastase inhibitor which would be useful for the treatment of human emphysema. A variety of structures will be investigated including heterocyclic structures which may be transition state analogs, peptides analogs which may form tetrahedral intermediates with elastase, suicide inhibitors, and possibly selective acylating agents. All inhibitors will be tested with catepsin G and other chymotrypsin-like enzymes. This will yield information on the specificity of the inhibitors and may produce new inhibitor structures for chymotrypsin-like enzymes. Any promising inhibitors will be provided to other investigators for studies in animal models of emphysema. This research should lead to a better understanding of the active site structures of the enzymes involved in connective tissue turnover and should lead to new therapeutic methods forthe treatment of pulmonary emphysema.